Dietary restriction (DR), a reduction of nutrients in the diet, provides the most robust method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. It has been shown in rodents that DR protects against a number of age-related diseases including Huntington's, cancer, diabetes and other cardiovascular diseases. Given the universally protective effects of DR, investigating its molecular mechanisms will promote a greater understanding of the pathogenesis of various human age-related diseases, which will in turn help advance the development of therapeutics for these disorders. Due to their short lifespan and ease of genetic manipulation, invertebrate models continue to be useful as models for understanding human diseases and in providing therapeutic targets. Given the conservation of biological processes and signaling pathways, studies in model organisms are likely to make the greatest contributions to our understanding of biological mechanisms of lifespan extension by DR. Using an interdisciplinary approach which combines genetics, genomics and biochemistry techniques we propose to examine how DR extends lifespan in flies. The Kapahi lab previously identified the TOR (target of rapamycin) pathway as a critical regulator of nutrient modulated lifespan changes in flies. This genetic pathway plays a conserved role in sensing nutrients in yeast, worms, flies and humans. Building upon the knowledge that nutrients play a key role in modulating mRNA translation, the conversion of RNA to protein, this proposal tests the hypothesis that differential mRNA translation downstream of 4EBP plays a key role in determining lifespan. The Kapahi laboratory has identified that a fly mutant defective in modulating mRNA translation upon changes in nutrients in the diet also fails to show the extension in lifespan normally observed under DR. This suggests that modulating mRNA translation is a key mechanism that determines longevity. Using a novel methodology that measures the mRNA translation state at the genome wide level, the lab has identified significant changes in mitochondrial genes that regulate metabolism upon DR. This data suggests that under DR, flies switch to a metabolic state that allows more efficient utilization of energy;this proposal examines the role of this switch in metabolic function and other differentially translated genes in regulating lifespan upon DR. PUBLIC HEALTH RELEVANCE: Dietary restriction is the most robust environmental method of lifespan extension in various species and has been shown to protect against various age-related diseases including diabetes, cancer and neurodegeneration. This proposal investigates the mechanism by which TOR (target of rapamycin) mediates the lifespan extension effects by dietary restriction using Drosophila. Our findings will have a significant effect on understanding the role of nutrition in aging and age-related diseases in humans.